Our long-term goal is to develop novel strategies to reduce post- asphyxial neurologic sequelae in newborn infants by focusing on interactions of the post-ischemic immature brain with the complement system. Annually in the U.S.A, acute hypoxic-ischemic cerebral injury occurs in approximately 14,000 newborn infants who experience a significant reduction in blood flow and oxygenation during birth (birth asphyxia). Fifty percent die and one-third of the survivors develop mental retardation and/or developmental disabilities. Previous studies indicate that much of the cellular destruction in the brain occurs during recovery after the reestablishment of cerebral blood flow. However, the mechanisms underlying this reperfusion injury are incompletely understood and must be defined before rational preventive strategies can be developed. Despite convincing evidence that complement-mediated cytotoxicity participates in injury to post-ischemic heart, liver, and intestines, a possible pathogenic role for complement in post-ischemic cerebral damage has only recently been suggested. C3 is an essential component of both classical and alternative pathways of complement activation. Component C9 polymerizes to form lethal pores on the surface of target cells during assembly of the cytolytic membrane attack complex of complement. We propose to develop a model in the immature rat to test the hypothesis that complement activation is a potentially treatable mechanism which participates in reperfusion injury to the post-ischemic immature brain. Three specific aims supported by preliminary studies seek to discover: 1)whether the deposition of C3 and C9 affects the survival of cultured oligodendrocytes during incubation with neonatal serum; 2) whether the deposition of C3 and C9 affects the survival of various post-ischemic cerebral cells in vivo; 3) the effects of complement inhibition in the above in vitro and in vivo systems. Preliminary studies suggest that serum from neonatal humans or rats contain sufficient complement activity to kill neonatal rat oligodendrocytes and that complement inhibition protects the cells in vitro. Also, preliminary studies indicate that C3 and C9 are present on post-ischemic cerebral cells of immature rats that the prophylactic administration of complement inhibitors such as cobra venom factor blocks deposition of these complement components and may possibly reduce the incidence of cerebral infraction. The results of the proposed studies may facilitate development of new strategies, such as the administration of complement inhibitors, to reduce the mortality, mental retardation, and developmental disabilities associated with birth asphyxia.